We present the mean volumes and standard deviations for each of the Brodmann areas by group in a supplementary table (Table-2)
. Our hypothesis-driven MANOVA results are presented below.
3.1 Cingulate gyrus arch volume
A Group×Cingulate Brodmann area (BA25,24,31,23,29)×Matter type×Hemisphere MANOVA examined whether there were schizophrenia-spectrum differences in cingulate gyrus volume. Compared with healthy controls, both SPD and schizophrenia patients had significantly less gray matter volume (mean±SD: healthy controls=0.226± 0.024, SPD=0.215±0.018, schizophrenia=0.218±0.023), SPDs had significantly greater white matter volume and the two patient groups did not differ from each other (healthy controls=0.226±0.024, SPD=0.233±0.018, schizophrenia=0.230±0.023; Significant Group × Matter type interaction (F[2,281]=7.44, p=0.0007, Wilks; significant post-hoc comparisons were p<0.002).
Compared with healthy controls, the schizophrenia patients displayed the greatest reduction in cingulate volume in BA24 and SPD patients were intermediate, although none of the follow-up tests reached significance (). The gray/white matter effect was largest for BA24, 31, and 23 (). Follow-up tests revealed that both patient groups had significantly less gray and more white matter in BA31. SPD patients also showed reduced gray but increased white matter in BA24 and BA23 (all p<0.04, LSD). Schizophrenia patients had significantly reduced gray matter in BA31. White matter volume in BA24 was significantly greater in SPD than schizophrenia patients and this was the only cingulate region where the patient groups differed (p=0.002, LSD). The main effect of group (p=0.46) and none of the other interactions with group reached significance.
Figure 2 Differences from normal in cingulate gyrus Brodmann area volumes are shown for the schizophrenia spectrum groups. Compared with healthy controls, the schizophrenia patients showed the greatest cingulate volume reduction in BA 24 and SPD patients were (more ...)
Figure 3 Differences from normal in gray/white matter volume in the cingulate gyrus showed significantly decreased gray and increased white matter volume in the schizophrenia-spectrum groups (Group × Matter type × Brodmann area interaction for (more ...)
3.2 Anterior, orbital, and dorsolateral prefrontal cortex volume
A Group×Rregion (Anterior: BA 8,9,10; Orbital: BA 11,12,47; Dorsolateral: BA 44,45,46)×Brodmann area×Matter type×Hemisphere MANOVA examined whether schizophrenia-spectrum differences existed within prefrontal cortex. The schizophrenia patients had significantly reduced overall gray (p=0.000013) but not white matter volume in prefrontal cortex (averaged across hemisphere and all BAs) compared with the controls and SPD patients (). Compared with healthy controls, schizophrenia patients had reduced volume in the anterior region of the prefrontal cortex, especially BA10, (p=0.003, LSD test) while SPD patients showed greater-than-normal BA10 volume (). In the right hemisphere, both patient groups showed reduced prefrontal volume while in the left hemisphere, schizophrenia but not SPD patients showed reduced volume, predominantly in the anterior prefrontal region (BA8, 9, and 10; Group×Region×Hemisphere interaction, F[4,560]=5.41, p=.0003, Group×Hemisphere interaction, F[2,281]=3.96, p=.02). Neither the main effect of group (p=0.15), nor any of the other interactions with group were significant.
Figure 4 Gray and white matter prefrontal cortex volume differences from normal are shown for the schizophrenia-spectrum groups. The schizophrenia patients showed significantly reduced gray matter volume in prefrontal cortex (averaged across hemisphere and all (more ...)
Figure 5 Significant Group × Region × Brodmann area interaction (F[8,556]=7.48, p=0.000001) is shown. *C>Sz patients, p=0.003, Fisher’s LSD test. +SPD>Sz patients, p=0.0001, Fisher’s LSD test. The Group × (more ...)
3.3 Temporal lobe (BA22, 21, and 20) volume
A Group×Region(superior: BA22, middle: BA21, and inferior temporal gyrus: BA20)×Matter type×Hemisphere MANOVA was conducted to examine group differences in the temporal cortex. There was a highly significant main effect of group which indicated a spectrum pattern with Healthy controls>SPD>Schizophrenia patients for average relative temporal lobe volume (F[2,281]=5.14, p=0.006; Controls: mean=0.659±0.042, SPD patients: mean=0.649±0.044, Schizophrenia patients: mean=0.638±0.048). This spectrum pattern was found in the left hemisphere but in the right hemisphere, the schizophrenia patients showed reduced volume and the SPD patients were similar to normal (Group×Hemisphere interaction, F[2,281]=10.60, p=0.00004). A Group×Matter type interaction indicated a spectrum pattern for temporal lobe gray matter with C>SPD>Sz and the opposite Sz>SPD>C for white matter (F[2,281]=12.67, p=0.000005). Compared with controls, both patient groups showed reduced gray matter volume in the middle temporal gyrus, only the schizophrenia patients showed reduced gray matter volume in superior and inferior temporal gyrus, and SPD patients showed increased white matter volume in the inferior temporal gyrus ().
Figure 6 (TOP) A significant Group × Brodmann area × Matter type interaction (F[4,560]=5.89, p=0.0001) was observed in the temporal lobe. *significantly different from healthy controls, all p values between 0.04-0.000001, 1SPD>Sz patients, both (more ...)
In the superior temporal gyrus, the schizophrenia patients (p=0.03, LSD test) but not the SPD patients showed significantly reduced volume in the left hemisphere compared to normal. In the middle temporal gyrus, both patient groups showed significantly reduced left (both p<0.013) but not right volume. In the inferior temporal gyrus there were no group differences in laterality ().
Figure 6 (BOTTOM) Group × Brodmann area × Hemisphere interaction, F[4,560]=2.79, p=0.026. *significantly different from healthy controls, all p values<0.04, Fisher’s LSD test. A Group×Brodmann area interaction (collapsed across gray/white (more ...)
3.4 Absolute brain volume
The three groups did not differ on total brain volume (Controls: mean=1216cm3±SD=125; SPD patients: mean =1205cm3±125, schizophrenia patients: mean= 1214cm3±100, F[2,281]=0.20, p=0.82). Total brain volume was determined by adding the volume of gray and white matter for all Brodmann regions across the 33 coronal slices.
In order to examine whether the three groups differed in absolute volume for the four lobes, we conducted a Group×Lobe (frontal, parietal, temporal, occipital)×Matter type×Hemisphere MANOVA. Brodmann areas included for each lobe were as follows: frontal lobe: BA8,9,10,11,12,32,44,45,46, and 47; parietal lobe: BA7,39, and 40; temporal lobe: BA20,21,22,27,28,30,35,36,37,38,41, and 42; and occipital lobe: BA17,18, and 19. The groups did not differ in overall absolute volume (collapsed across all lobes, matter type, and hemisphere), F[2, 281]=1.27, p=0.28. Compared with the healthy controls, the schizophrenia patients showed significantly reduced gray matter volume in all four lobes, however, the temporal lobe reduction (p<0.004, LSD test) was most striking and more prominent in the left hemisphere (Group×Lobe interaction (F[6,558]=2,41, p=0.026; Group×Lobe×Hemisphere interaction, F[6,558]=2.49, p=0.02). Schizophrenia patients showed small increases in white matter in all four lobes compared with healthy controls. In contrast, SPD patients showed more mild gray matter reductions in frontal, parietal, and temporal cortex, and none in occipital cortex (Group×Lobe×Matter type interaction, F[6,558]=4.12, p<0.0005; ). The Group×Matter type interaction confirmed a spectrum pattern showing controls had greater overall gray matter volume averaged across the four lobes, schizophrenia patients had the least, and SPD patients were intermediate, while the pattern was reversed for white matter volume with schizophrenia patients having the greatest white matter volume (F[2,281]=9.74, p=0.00008). A Group×Hemisphere interaction indicated that overall volume shrinkage was marked in both the left and right hemispheres in schizophrenia while SPD patients were intermediate between healthy controls and schizophrenia patients in the left hemisphere, but similar to normal in the right (F[2,281]=8.37, p<0.0003). A MANOVA on relative volume for the four lobes produced the same pattern of significant group differences (e.g., Group×Lobe×Matter type interaction, F[6,558]=4.20, p<0.0004).
Group × Lobe × Matter type interaction, F[6, 558]=4.12, p=0.00047, *p=0.0036, Fisher’s LSD test.
3.5 Symptom correlates
To minimize the number of tests, we conducted volume vs. clinical symptom correlations with only the seven BAs in prefrontal and temporal cortex where we found significant between-group volume differences (i.e. significant interactions with Group: BA24, 8, 9, 10, 22, 21, and 20).
Among the schizophrenia patients, smaller gray and larger white matter volume in fronto-temporal BAs was associated with greater severity of BPRS negative symptoms (). In contrast, individual differences in positive symptom severity was generally not associated with cortical volume.
BPRS Symptom correlates of gray and white matter volume in schizophrenia patients.
Only two of the seven BAs examined showed significant correlations in the SPD group. Smaller gray matter volume in BA24 was associated with greater interpersonal impairment (r=−0.31, p=.007). Smaller white matter volume in BA22 (STG) was associated with greater cognitive impairment (r=−0.25, p=.026).